Elastin-derived Scaffolds for Tissue Engineered Small Diameter Vascular Grafts

用于组织工程小直径血管移植物的弹性蛋白支架

• 批准号: 8274427
• 负责人: Dan TEODOR Simionescu
• 金额: $ 5.5万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274427
• 关键词: Abdomen; Anastomosis - action; Animal Model; Animals; Aorta; Arteries; Autologous; Biocompatible Materials; Biological; Biomechanics; Biomedical Engineering; Blood; Blood Cells; Blood Vessels; Bypass; Caliber; Cardiovascular system; Cells; Clinical; Collaborations; Coronary Artery Bypass; Developing Countries; Development; Disease; Dreams; Elasticity; Elastin; Elements; Endothelial Cells; Endothelium; Engineering; Evaluation; Exhibits; Family suidae; Future; Glucose; Grant; Harvest; Head; Healed; Healthcare; Human; Human body; Hyperplasia; Implant; Injury; Legal patent; Life; Mechanics; Modeling; One-Step dentin bonding system; Operative Surgical Procedures; Outcome; Patients; Pentas; Peripheral; Pilot Projects; Polytetrafluoroethylene; Porosity; Positioning Attribute; Procedures; Process; Property; Proteins; Public Health; Rattus; Research; Research Personnel; Resistance; Rodent Model; Scientist; South Africa; Supporting Cell; Surface; Surgeon; Testing; Thick; Thrombosis; Tissue Engineering; Translating; Translations; Transplanted tissue; Tube; United States National Institutes of Health; Universities; Vascular Diseases; Vascular Graft; Veins; Work; angiogenesis; base; biomaterial compatibility; clinical application; clinically relevant; healing; implantation; improved; innovation; insight; interdisciplinary approach; lecturer; novel; novel strategies; pressure; professor; renal artery; scaffold; subcutaneous

DESCRIPTION (provided by applicant): More than 1 million small diameter vascular grafts are needed every year for peripheral or coronary bypass surgery. The conduit of choice is an autologous vein or artery, but these are not always available due to pre-existing conditions or previous harvesting. Commercially available biomaterials such as expanded polytetrafluoroethylene (ePTFE) function well as large diameter vascular grafts in the first 5 years but fail dramatically thereafter because of incomplete healing and lack of a protective endothelial layer. Clinical use of ePTFE grafts below 6 mm in diameter is associated with a high rate of narrowing at the proximal anastomosis and ultimately occlusion due to thrombosis and intimal hyperplasia. Thus, new biomaterials capable of supporting a luminal endothelial layer are needed for development of functional small diameter vascular grafts. This study is highly relevant to public health because vascular disease is a very important chapter of health care in the US as well as in third world countries such as South Africa. Long term objective: To develop "off-the-shelf" small diameter grafts that would promote formation of a stable, shear-resistant, endothelial layer to protect the graft from occlusion. Spontaneous luminal coverage with endothelial cells after implantation may occur via two independent mechanisms: 1) Trans-anastomotic endothelialization, whereby endothelial cells migrate laterally across the anastomosis to cover the luminal graft surface and 2) Trans-mural endothelialization, an angiogenic process by which endothelial cells migrate through the thickness of the scaffold to establish a neo-intima. Since trans-anastomotic endothelialization appears to be limited in human implants (as compared to animal models), both mechanisms will be investigated in proposed studies. Working hypothesis: Patent small diameter vascular grafts can be produced by engineering elastin scaffolds that promote endothelialization after implantation. The PI at Clemson University is developing porous elastin-derived vascular grafts (EDVGs) and treatment with penta-galloyl-glucose (PGG) for reversible stabilization. EDVGs were found to be non-thrombogenic in short term implantation studies, exhibited adequate elasticity, burst pressure and compliance, and also degraded slowly, facilitating healing and supporting cell repopulations in subcutaneous studies. Approach: Elastin conduits prepared in the PI's group will be implanted at the University of Cape Town into the rat infrarenal aorta to assess: (i) biocompatibility, patency and ability to support trans- anastomotic endothelialization (Aim 1), and (ii) trans-mural endothelialization in an isolated composite loop model developed by the University of Cape Town whereby the test segment is interposed in between two sections of ePTFE graft material before implantation (Aim 2). After evaluation in the rodent models, EDVGs will be implanted as carotid interposition grafts in pigs, a more clinically relevant large animal model (Aim 3). Demonstration of patency and endothelialization of these elastin-derived scaffolds has great potential for future clinical applications. The proposed research will be performed primarily in the Cardiovascular Research Unit, University of Cape Town, South Africa, in collaboration with Dr. Deon Bezuidenhout, senior lecturer and Professor Peter Zilla, head of department, both acting as co-investigators, as a logical extension of NIH grants R01HL093399 (PI, Dr. Dan Simionescu) and R21EB009835 (PI, Dr. Agneta Simionescu, co-investigator for this proposal), during the period 01/01/2011 to 12/31/2013.

描述（申请人提供）：每年需要100多万例小直径血管移植用于周围或冠状动脉搭桥手术。选择的导管是自体静脉或动脉，但由于先前存在的条件或先前的收获，这些并不总是可用的。商业上可用的生物材料，如膨胀聚四氟乙烯（ePTFE），在前5年内可以很好地用于大直径血管移植物，但由于不完全愈合和缺乏保护性内皮层，之后就会显著失败。临床使用直径小于6mm的ePTFE移植物与高发生率的近端吻合口狭窄和最终闭塞有关，原因是血栓形成和内膜增生。因此，需要能够支持管腔内皮层的新型生物材料来开发功能性小直径血管移植物。这项研究与公共卫生高度相关，因为血管疾病是美国以及南非等第三世界国家卫生保健的一个非常重要的章节。长期目标：开发“现成的”小直径移植物，促进形成稳定，抗剪切的内皮层，以保护移植物免受闭塞。植入后内皮细胞自发覆盖管腔可能通过两种独立的机制发生：1)跨吻合口内皮化，即内皮细胞沿吻合口横向迁移，覆盖移植物管腔表面；2)跨壁内皮化，即血管生成过程，内皮细胞沿支架厚度迁移，建立新内膜。由于经吻合口内皮化在人类植入物中似乎有限（与动物模型相比），这两种机制都将在拟议的研究中进行调查。工作假设：采用工程弹性蛋白支架，促进血管植入后内皮化，可制备小直径血管移植物。克莱姆森大学（Clemson University）的PI正在开发多孔弹性蛋白衍生血管移植物（edvg），并使用五没糖酰葡萄糖（PGG）进行治疗，以实现可逆稳定。在短期植入研究中发现edvg无血栓形成性，表现出足够的弹性、破裂压力和顺应性，并且降解缓慢，在皮下研究中促进愈合和支持细胞再生。方法：PI组制备的弹性蛋白导管将在开普敦大学（University of Cape Town）植入大鼠肾下主动脉，以评估：(i)生物相容性、通畅性和支持经吻合口内皮化的能力（Aim 1），以及（ii）在开普敦大学（University of Cape Town）开发的分离复合环模型中进行跨壁内皮化，在植入前将测试段插入两段ePTFE移植材料之间（Aim 2）。在啮齿动物模型中进行评估后，edvg将作为颈动脉间置移植物植入猪，这是一种更具有临床意义的大型动物模型（Aim 3）。证明这些弹性蛋白衍生支架的通畅性和内皮化在未来的临床应用中具有很大的潜力。拟议的研究将主要在南非开普敦大学心血管研究部门进行，与高级讲师Deon Bezuidenhout博士和系主任Peter Zilla教授合作，作为NIH资助R01HL093399 （PI， Dan Simionescu博士）和R21EB009835 （PI， Agneta Simionescu博士，本提案的共同研究者）的逻辑延伸，时间为2011年1月1日至2013年12月31日。